Publications by authors named "Monica Marta"

53 Publications

Cerebrospinal fluid HIV RNA escape symptomatology.

AIDS 2021 Jun 15. Epub 2021 Jun 15.

Mildmay Hospital, London, UK Unit of Infectious Diseases, San Raffaele Hospital, Milan, Italy Section of Retrovirology, Department of Infectious Disease, Faculty of Medicine, Imperial College London, London, UK Department of HIV Medicine, St. Mary's Hospital, Imperial College Healthcare NHS Trust, London, UK Unit of Neuroradiology, ASST Papa Giovanni XXIII, Bergamo, Italy Lazzaro Spallanzani National Institute of Infectious Diseases, Rome, Italy San Paolo Hospital, University of Milan, Milan, Italy University of Bari, Bari, Italy Unit of Infectious Diseases, Department of Medical Sciences, University of Turin, Turin, Italy Department of Neurology, St. Mary's Hospital, Imperial College Healthcare NHS Trust, London, UK Neurosciences, Blizard Institute, Queen Mary University of London, London, UK Grahame Hayton Unit, I&I and Neurology Department, Barts Health NHS Trust, London, UK.

Objective: To characterise the clinical, laboratory and radiological characteristics of persons with HIV (PWH) presenting with cerebrospinal fluid (CSF) HIV RNA escape.

Design: Retrospective case review of PWH presenting with symptomatic CSF HIV RNA escape at seven tertiary HIV clinical sites in UK and Italy.

Method: PWH with symptomatic CSF HIV RNA escape episodes were identified and data obtained from medical records. CSF HIV RNA escape was defined as quantifiable CSF HIV RNA in unquantifiable plasma HIV RNA or CSF HIV RNA greater than plasma HIV RNA in cases where plasma HIV RNA was quantifiable. The onset of clinical symptoms was classified as acute (<2 weeks-6 months), or chronic (>6 months) and differences in presentation in those with CSF HIV RNA below and above 1000 copies/mL determined.

Results: We identified 106 PWH with CSF HIV RNA escape (65 male); 68 (64%) PWH had acute presentations and 38 (36%) had chronic presentations. Cognitive decline (n = 54, 50.9%), confusion (n = 20, 18.9%) and headache (n = 28, 26.4%) were the most common presentations, with cognitive decline being more common in PWH who presented chronically compared with PWH who presented acutely (73.7% vs 35.3%, p = 0.0002). Sixty PWH had CSF HIV RNA ≥1000 copies/mL and presented more frequently with confusion (n = 15/60, 25.0%) compared to PWH with CSF HIV RNA <1000 copies/mL at presentation (n = 5/46, 10.9%; p = 0.03).

Conclusion: Cognitive decline, confusion and headache are the most frequent presenting symptoms of CSF HIV RNA escape and their relative frequency varied according to symptom onset and CSF HIV RNA concentration.
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http://dx.doi.org/10.1097/QAD.0000000000002992DOI Listing
June 2021

Music as Add-On Therapy in the Rehabilitation Program of Parkinson's Disease Patients-A Romanian Pilot Study.

Brain Sci 2021 Apr 29;11(5). Epub 2021 Apr 29.

Department of Neuroscience, "Iuliu Hatieganu" University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania.

Music has been proven to have therapeutic potential in neurological disorders, especially Parkinson's disease (PD), since rhythmic auditory cueing can partially replace the progressive loss of rhythmicity and automaticity. Several reports have highlighted improvements in motor outcomes in PD patients undergoing music therapy, but only a few studies have evaluated non-motor outcomes, such as quality of life (QoL), which deteriorates with disease progression. The current pilot study aims to examine the effects of a multimodal rehabilitation program centered on physical therapy combined with listening to music on self-reported QoL in people with PD, compared to the same rehabilitation program alone. The study was conducted on patients with idiopathic PD who attended a specific rehabilitation program with a duration of 2.5 h daily for 14 days. The patients were divided into the study group (16 patients), who listened to background music during the rehabilitation program sessions, and the control group who did not listen to music during sessions. The patients were assessed using the self-report Parkinson's Disease Questionnaire (PDQ-39) at the beginning of the program and 1 month after its initiation. The patients in the study group registered greater improvements in five of the eight areas of life assessed by PDQ-39 compared to the control group. In conclusion, listening to music combined with a multimodal rehabilitation program centered on physical therapy may be beneficial for the patients' quality of life.
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http://dx.doi.org/10.3390/brainsci11050569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145473PMC
April 2021

Partnering bevacizumab with irinotecan as first line-therapy of metastatic colorectal cancer improves progression free survival-A retrospective analysis.

PLoS One 2021 28;16(4):e0248922. Epub 2021 Apr 28.

Department of Mother and Child, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.

Colorectal cancer remains one of the most frequent malignancies (third place at both genders) worldwide in the last decade, owing to significant changes in modern dietary habits. Approximately half of the patients develop metastases during the course of their disease. The available therapeutic armamentarium is constantly evolving, raising questions regarding the best approach for improving survival. Bevacizumab remains one of the most widely used therapies for treating metastatic colorectal cancer and can be used after progression. This study aimed to identify the best chemotherapy partner for bevacizumab after progression. We performed a retrospective analysis of patients with metastatic colorectal cancer who were treated with bevacizumab as first- and second-line chemotherapy. Data were collected for 151 patients, 40 of whom were treated with double-dose bevacizumab after the first progression. The two standard chemotherapy regimens combined with bevacizumab were FOLFIRI/CAPIRI and FOLFOX4/CAPEOX. The initiation of first-line treatment with irinotecan-based chemotherapy improved progression-free survival and time to treatment failure but not overall survival. After the first progression, retreatment with the same regimen as that used in the induction phase was the best approach for improving overall survival (median overall survival: 46.5 vs. 27.0 months for the same vs. switched strategy, respectively). No correlations were observed between the dose intensity of irinotecan, oxaliplatin, 5-fluorouracil, or bevacizumab and the overall survival, progression-free survival in the first-/second-line treatment, and time to treatment failure. Interaction between an irinotecan-based regimen as a second-line treatment and double-dose bevacizumab after progression was associated with an improved overall survival (p = 0.06). Initiating systemic treatment with an irinotecan-based regimen in combination with bevacizumab improved the progression-free survival in the first-line treatment and time to treatment failure. In terms of overall survival, bevacizumab treatment after the first progression is better partnered with the same regimen as that used in the induction phase.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248922PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081186PMC
April 2021

Doubling the Dose of Bevacizumab Beyond Progression in Metastatic Colorectal Cancer-the Experience of a Tertiary Cancer Center.

Front Pharmacol 2021 11;12:487316. Epub 2021 Mar 11.

Department of Mother and Child, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.

Colorectal cancer (CRC) is the third most common cancer in Europe, with an annual increase in incidence ranging between 0.4 and 3.6% in various countries. Although the development of CRC was extensively studied, limited number of new therapies were developed in the last few years. Bevacizumab is frequently used as first- and second-line therapy for management of metastatic CRC (mCRC). The aim of this study is to present our experience with using bevacizumab beyond disease progression at different dosage levels in mCRC patients, in terms of overall survival, progression-free survival, time to treatment failure, and toxicities. We performed a consecutive retrospective analysis of patients with confirmed mCRC who were treated with bevacizumab at "Prof Dr. Ion Chiricuta" Institute of Oncology, Cluj-Napoca, Romania. We included patients who had received bevacizumab as first- or second-line therapy and further stratified them according to the dose administered as a second-line (either standard dose of 5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks, or double dose of 10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks-depending on the classical chemotherapy partner). All patients had received bevacizumab beyond progression (BYP) which is defined as continuing bevacizumab administration through second-line treatment despite disease progression. In each group, we evaluated the prognostic factors that influenced survival and treatment outcome. One hundred and fifty-one (151) patients were included in the study. Themedian age of patients receiving double dose bevacizumab (DDB) and standard dose bevacizumab (SDB) was 58 years (range 41-71) and 57 years (range 19-75), respectively. The median overall survival in the DDB group was 41 months (range 27-49) compared to 25 months (range 23-29) in the SDB group ( = 0.01 log-rank test). First-line oxaliplatin-based treatment was used more frequently regardless of group, while irinotecan-based more frequently used as a second-line treatment ( = 0.014). Both oxaliplatin- and irinotecan-based regimens were found to be suitable partners for BYP. Statistical analysis revealed that dose intensity, primary tumor location, and cumulative exposure to BYP had significant influence on survival. Doubling the dose of bevacizumab after first progression may improve survival in mCRC patients. Increasing bevacizumab dose intensity could override the prognostic impact of primary tumor location in patients receiving double the dose of bevacizumab after first disease progression.
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http://dx.doi.org/10.3389/fphar.2021.487316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991840PMC
March 2021

Cognitive and Neurologic Rehabilitation Strategies for Central Nervous System HIV Infection.

Curr HIV/AIDS Rep 2020 10;17(5):514-521

Mildmay Hospital, 19 Tabernacle Gardens, London, E2 7DZ, UK.

Purpose Of Review: Cognitive impairment leading to disability is increasingly seen in people living with human immunodeficiency virus (PLWH). Rehabilitation can alleviate the effects of cognitive impairment upon function. The aim of this paper is to discuss the strategies that have been used in cognitive and neurologic rehabilitation in PLWH.

Recent Findings: Studies examining pharmacological and non-pharmacological strategies were analysed. Medical management of HIV and co-morbidities should be optimised. Non-pharmacological strategies, including nerve stimulation techniques, exercise-based interventions, and paper and computer-based cognitive rehabilitation, have some evidence supporting their use in PLWH either as stand-alone interventions or as part of a multidisciplinary approach. Both pharmacological and non-pharmacological rehabilitation strategies have been used with PLWH. More intervention trials are needed to assess cognitive and neurological rehabilitation strategies and further evaluate their potential benefit in PLWH.
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http://dx.doi.org/10.1007/s11904-020-00515-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497368PMC
October 2020

CSF neurofilament light chain testing as an aid to determine treatment strategies in MS.

Neurol Neuroimmunol Neuroinflamm 2020 11 21;7(6). Epub 2020 Aug 21.

From the The Blizard Institute (S.R., I.S., D.H., K.C.-L., T.C., L.B., F.A., M.M., K.S., G.G., S.G.), Centre for Neuroscience, Surgery & Trauma, Barts and The London School of Medicine and Dentistry, Queen Mary University of London; and Clinical Board Medicine (Neuroscience) (S.R., I.S., B.T., M.M., K.S., G.G., S.G.), The Royal London Hospital, Barts Health NHS Trust, London, UK.

Objective: To evaluate the use of CSF neurofilament light chain (NfL) measurements in clinical practice as well as their effect on treatment strategies and outcomes in patients with MS.

Methods: This was an observational cohort study of patients with MS who had a CSF NfL measurement between December 2015 and July 2018 as part of their routine clinical care. Treatment strategies were classified as "No Treatment/No Escalation" (no treatment or no escalation of treatment) or "Treatment/Escalation" (first-line injectable/oral disease-modifying therapies (DMTs), highly active DMTs, or treatment escalation). Change in Expanded Disability Status Scale (EDSS) scores was evaluated after 1-year follow-up.

Results: Of 203 patients with MS, 117 (58%) had relapsing-remitting MS. Disease activity was most frequently indicated by elevated CSF NfL (n = 85), followed by clinical (n = 81) and MRI activity (n = 65). CSF NfL measurements were independently associated with clinical ( = 0.02) and MRI activity ( < 0.001). Of those with elevated CSF NfL as the only evidence of disease activity (n = 22), 77% had progressive MS (PMS). In patients with PMS, 17 (20%) had elevated CSF NfL as the sole indicator of disease activity. Elevated CSF NfL resulted more frequently in Treatment/Escalation than normal CSF NfL ( < 0.001). Median EDSS change at follow-up was similar between patients receiving No Treatment/No Escalation and Treatment/Escalation decisions ( = 0.81).

Conclusions: CSF NfL measurements informed treatment strategies, alongside clinical and MRI measures. CSF NfL levels were the only indicator of disease activity in a subset of patients, which was more pronounced in patients with PMS. Elevated CSF NfL was associated with more Treatment/Escalation strategies, which had an impact on EDSS outcomes at 1 year.
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http://dx.doi.org/10.1212/NXI.0000000000000880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455313PMC
November 2020

Serum neurofilament-light concentration and real-world outcome in MS.

J Neurol Sci 2020 Oct 3;417:117079. Epub 2020 Aug 3.

Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Wales, UK; Helen-Durham Neuroinflammatory Unit, University Hospital of Wales, Cardiff, Wales, UK. Electronic address:

Background: Prognostication in multiple sclerosis (MS) remains challenging. Biomarkers capable of providing this information at diagnosis would be valuable in shaping therapeutic decisions. Measurement of neurofilament light (NfL) has shown promise in predicting clinical outcomes in established MS, but its ability to predict outcomes in real-world cohorts at diagnosis requires further validation.

Methods: We used linear regression to evaluate the relationship between serum NfL (sNfL), measured at the time of diagnosis with short-term (1-year) and medium-term (5-year) clinical outcomes in 164 people with MS from a real-world, population-based cohort. Cox proportional hazards regression was used to analyse the association between sNfL and subsequent hazard of relapse or sustained accumulation of disability (SAD). Analyses were adjusted for age and disease-modifying treatment (DMT).

Results: sNfL concentration at diagnosis was modestly associated with baseline EDSS score (β = 0.272, 95% CI 0.051 to 0.494, p = 0.016). However, no significant associations were found between baseline sNfL and odds of relapse at 12-months, 5-year EDSS change, or the hazard of relapse or SAD over 5 years follow-up. Dichotomising baseline sNfL according to the median sNfL did not change these findings.

Conclusions: sNfL appears to be of limited clinical utility in predicting future irreversible neurological disability in a largely untreated real-world population, and remains insufficiently validated to shape treatment decisions at the time of diagnosis. Further studies may be needed for sNfL to be considered as a prognostic marker in the MS clinic. However the masking effect of DMTs on the natural disease trajectory will continue to pose challenges.
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http://dx.doi.org/10.1016/j.jns.2020.117079DOI Listing
October 2020

Sex effects across the lifespan in women with multiple sclerosis.

Ther Adv Neurol Disord 2020 1;13:1756286420936166. Epub 2020 Jul 1.

Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany.

Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating central nervous system disorder that is more common in women, with onset often during reproductive years. The female:male sex ratio of MS rose in several regions over the last century, suggesting a possible sex by environmental interaction increasing MS risk in women. Since many with MS are in their childbearing years, family planning, including contraceptive and disease-modifying therapy (DMT) counselling, are important aspects of MS care in women. While some DMTs are likely harmful to the developing fetus, others can be used shortly before or until pregnancy is confirmed. Overall, pregnancy decreases risk of MS relapses, whereas relapse risk may increase postpartum, although pregnancy does not appear to be harmful for long-term prognosis of MS. However, ovarian aging may contribute to disability progression in women with MS. Here, we review sex effects across the lifespan in women with MS, including the effect of sex on MS susceptibility, effects of pregnancy on MS disease activity, and management strategies around pregnancy, including risks associated with DMT use before and during pregnancy, and while breastfeeding. We also review reproductive aging and sexual dysfunction in women with MS.
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http://dx.doi.org/10.1177/1756286420936166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331774PMC
July 2020

The ocrelizumab phase II extension trial suggests the potential to improve the risk: Benefit balance in multiple sclerosis.

Mult Scler Relat Disord 2020 Sep 8;44:102279. Epub 2020 Jun 8.

Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, United Kingdom; Clinical Board:Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS Trust, London E1 1BB, United Kingdom.

Objective: Ocrelizumab inhibits relapsing multiple sclerosis when administered every six months. Based on potential similar memory B cell depletion mechanisms with cladribine and alemtuzumab, we hypothesised that CD20-depletion of B cells by ocrelizumab may exhibit a duration of response exceeding the current licenced treatment interval.

Methods: Internet-located information from regulatory submissions and meeting reports relating to the unpublished open-label, phase II ocrelizumab extension trial (NCT00676715) were reviewed. This followed people (54-55/arm) with MS, who switched from placebo or interferon-beta to ocrelizumab for three 600 mg treatment cycles (week 24, 48, 72) or people treated with ocrelizumab for four 600 mg treatment cycles (week 0-72), followed by an 18 month treatment-free period.

Results: CD19+ B cells were rapidly depleted within 2 weeks and slow CD19+ B cell repopulation began about 6 months after the last infusion with median-repletion of over 15 months. The reduced annualized relapse rate during the published efficacy study appeared to be maintained in the extension study and there were no new T1 gadolinium-enhancing or T2 lesions detected in the treatment-free period. Importantly, within these extension cohorts, there appeared to be fewer adverse events and infections events.

Conclusions: Ocrelizumab appears to induce durable relapsing disease inhibition, within 3 treatment cycles Therefore, it may be possible to reduce the frequency of dosing to maintain efficacy, whilst limiting infection and other risks associated with continuous immunosuppression and could allow more effective vaccination against new pathogens. Further studies are now clearly required to determine whether this data is robust.
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http://dx.doi.org/10.1016/j.msard.2020.102279DOI Listing
September 2020

Protecting people with multiple sclerosis through vaccination.

Pract Neurol 2020 Dec 6;20(6):435-445. Epub 2020 Jul 6.

Neuroscience and Trauma, Blizard Institute of Cell and Molecular Science, London, UK.

Vaccination is one of the most effective and cost-efficient methods for protecting people with multiple sclerosis (MS) from infections. However, use of vaccines has often been problematic because of misguided concerns that they may exacerbate the disease and/or that some disease-modifying therapies may influence the immune response to immunisations and/or their safety. People with MS risk higher morbidity and mortality from vaccine-preventable infections. It is, therefore, important to address any patient's reluctance to accept vaccination and to provide clear guidance for clinicians on which vaccinations to consider proactively. We have reviewed the current literature and provide recommendations regarding vaccines in adults with MS, including specific advice regarding vaccination safety in patients receiving-or going to receive-disease-modifying therapies, vaccination during pregnancy, pretravel counselling and patient education.
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http://dx.doi.org/10.1136/practneurol-2020-002527DOI Listing
December 2020

Treatment beyond progression in metastatic colorectal cancer: to double or not to double the dose of bevacizumab?

J BUON 2020 Mar-Apr;25(2):875-883

Institute of Oncology, "Prof. Dr. Ion Chiricuta", Cluj-Napoca, Romania.

Purpose: Bevacizumab or cetuximab represent the standard treatment in association with classical chemotherapy in confirmed metastatic colorectal cancer (mCRC). Bevacizumab could be continued after the first disease progression with an overall survival (OS) advantage, compared to chemotherapy alone, but the optimal dose remains a debatable issue.

Methods: In a retrospective analysis of mCRC patients treated with bevacizumab, we selected patients with administration beyond progression, and stratified them according to the dose received- same dose bevacizumab (SDB) as first-line chemotherapy or double dose bevacizumab (DDB). For each group we evaluated OS, time to treatment failure (TTF) and progression-free survival in the first-line (PFS1) and in the second-line (PFS2).

Results: In the first-line therapy, oxaliplatin backbone regimen was used in 73% SDB, compared with 22.5% DDB patients, while irinotecan was used in 75% DDB and 27% SDB patients. Second-line oxaliplatin was given to 50% DDB and 29.7% SDB patients, while irinotecan was administered to 47.5% DDB and 70.3% SDB patients. The median values were: OS - 41 months in the DDB group and 25 months in the SDB group (p = 0.01); TTF - 24 months in the DDB group and 19 months in the SDB group (p=0.009); PFS1 - 17 months in the DDB group and 12 months in the SDB group (p=0.008); PFS2 - 9 months in the DDB group and 5 months in the SDB group (p = 0.03).

Conclusions: Doubling the dose of bevacizumab at progression seems to provide OS and PFS advantage for mCRC patients.
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February 2021

Socioeconomic status and disease-modifying therapy prescribing patterns in people with multiple sclerosis.

Mult Scler Relat Disord 2020 Jun 24;41:102024. Epub 2020 Feb 24.

Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark St, Whitechapel, London, E1 2AT, United Kingdom; Department of Neurology, Royal London Hospital, Barts Health NHS Trust, 7000 Whitechapel Road, Whitechapel, London, E1 1FR, United Kingdom.

Aims: To examine the association between socioeconomic status (SES) and disease-modifying therapy (DMT) prescribing patterns in people with relapsing-remitting multiple sclerosis (pwRRMS).

Methods: A cross-sectional analysis was conducted among pwRRMS treated with a DMT in the neuroinflammation service at The Royal London Hospital (Barts Health NHS Trust). Study data were collected between July and September 2017. SES was determined by patient income and education extracted from the English Index of Multiple Deprivation. Based on their efficacy, DMTs were categorized as moderate efficacy (Glatiramer Acetate and Beta-Interferons), high efficacy (Cladribine, Fingolimod and Dimethyl Fumarate) and very-high efficacy therapies (Natalizumab and Alemtuzumab). Multinomial logistic regressions were performed for univariate and multivariate models to assess differences between SES and DMT prescribing patterns.

Results: Treatment consisted of moderate efficacy (n = 76, 12%), high efficacy (n = 325, 51.3%) and very-high efficacy therapies (n = 232, 36.7%). Medians for income and education deciles were 4 (IQR 3-7) and 6 (IQR 4-8), respectively. After multinomial logistic regression analysis, patient income was not associated with increased odds of being treated with high efficacy (OR, 0.92; 95% CI, 0.82-1.04; p = 0.177) or very-high efficacy DMTs (OR, 0.95; 95% CI, 0.85-1.06; p = 0.371). Similarly, patient education was not associated with being treated with high efficacy (OR, 0.91; 95% CI, 0.80-1.03; p = 0.139) or very-high efficacy therapies (OR, 0.92; 95% CI, 0.81-1.04; p = 0.188).

Conclusions: SES was not predictive of DMT prescribing patterns in pwRRMS. Whilst this appears reassuring within this universal health care setting, the same methodology needs to be applied to other MS services for comparison. Data could then be further interrogated to explore potential socioeconomic inequities in DMT prescribing patterns across the UK.
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http://dx.doi.org/10.1016/j.msard.2020.102024DOI Listing
June 2020

Gastric cancer: adjuvant chemotherapy versus chemoradiation. A clinical point of view.

J BUON 2019 Nov-Dec;24(6):2209-2219

Department of Oncology, "Iuliu Hațieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.

Gastric cancer represents one of the most severe cancers with poor overall survival. Despite the availability of published data on the efficacy of adjuvant treatment, the actual percentage of treated patients remains low. The toxicity of radiotherapy or chemotherapy regimens differ and clinicians need accessible tools in order to better select candidates for adjuvant treatment. In this review, we present published data from clinical trials and cancer registries that might be useful for properly balancing the efficacy and toxicity of adjuvant treatment in gastric cancer patients who underwent surgery with curative intent.
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June 2020

Visibility and representation of women in multiple sclerosis research.

Neurology 2019 04 20;92(15):713-719. Epub 2019 Mar 20.

From Blizard Institute (A.T., M.M., G.G.) and Preventive Neurology Unit, Wolfson Institute of Preventive Medicine (C.C., G.G., R.D.), Queen Mary University London; Department of Neurology (M.M., G.G., R.D.), Royal London Hospital, Whitechapel, London; Independent journalist (R.H.), London; and Department of Neurology (J.P.), John Radcliffe Hospital, Oxford, UK.

Objective: To establish the gender distribution of multiple sclerosis (MS) researchers across high-impact neurologic publications, MS-specific journals, and the European Committee for Treatment and Research in MS (ECTRIMS).

Methods: Journal editorial boards and contents were retrieved online to assess first-named and senior authors. Published tables of contents for each journal from 2017 were reviewed. Congrex, the ECTRIMS organizers, were contacted and speaker names were obtained from online abstracts to assess visible opinion leaders.

Results: A total of 2,080 articles were analyzed across 4 general neurology journals, and 452 across 2 MS journals. Overall, 36% of general neurology articles had a female first name author and 25% had a female senior author. In MS-specific journals, 44% of first authors and 35% of senior authors were female, with similar proportions of unique authors. There is limited female representation on the ECTRIMS executive board, but reasonable balance on Council. Almost 50% of attendees in 2017 were female, but only 35% of invited speakers.

Conclusions: There is substantial female drop-off between junior and senior research level across multiple areas. Strategies to support gender balance are urgently required, including developing mentorship schemes, ensuring gender balance in conferences, and thorough examination of the barriers facing female academics with direct challenges to address unconscious bias.
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http://dx.doi.org/10.1212/WNL.0000000000007276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511087PMC
April 2019

Treating the ineligible: Disease modification in people with multiple sclerosis beyond NHS England commissioning policies.

Mult Scler Relat Disord 2019 Jan 2;27:247-253. Epub 2018 Nov 2.

The Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, United Kingdom; Clinical Board: Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS Trust, London, United Kingdom. Electronic address:

Background: Whilst there is a broad selection of drugs licensed as disease modifying treatments (DMTs) for people with relapsing multiple sclerosis (pwRMS), access to DMTs remains restricted, particularly for people with progressive MS (pwPMS). Cladribine has shown efficacy at all stages of MS. Following withdrawal from the market of oral cladribine in 2011, partly due to issues associated with lymphopenia, and following a thorough risk assessment, we started using subcutaneously injected cladribine (Litak) to treat both pwRMS and pwPMS. Here, we report on the real life safety and tolerability of this treatment option.

Methods: Cladribine was offered to (i) pwRMS as a choice despite fulfilling NHS England (NHSE) criteria for licensed DMTs, and (ii) pwRMS and pwPMS not eligible for NHSE approved DMTs. To avoid lymphocyte depletion lower than 0.5 × 10/l (WHO grade 2) cladribine was administered using a personalised dosing scheme (30-40 mg in week 1; and another 0-30 mg in week 5 pending total lymphocyte count at week 4). Anti-viral prophylaxis was given from day 1 for 60 days. Patients approaching week 48 were given a second treatment cycle. Data collection included side effects, relapses, change in disability and MRI indices.

Results: Seventy-one pwMS (40 female, 31 male; 36 RMS, 35 PMS,) received at least one treatment cycle. Mean age for starting cladribine was 44 years (range 22-72 years), median EDSS was 5 (range 1-8.5). Maximum follow-up was 28 months. 35/71 pwMS were followed up for at least 20 weeks. These patients had a median EDSS of 5.0 (range 1.0-7.5) at baseline and 5.5 (range 1.0-8.0) after a mean follow-up of 11 months (range 5-28). Cladribine was well tolerated with very few treatment-related adverse events observed. Personalised dosing led to grade 1-2 lymphopenia in 50% of cases. A single patient developed transient grade 3 lymphopenia. No cases of varicella or other infections were observed. Four/17 people with relapsing MS, experienced a total of six relapses during a mean follow-up of 13 months (range 5-28 months). In people with PMS (n = 18) median EDSS was 5.5 (2.0-7.5) at baseline and 6.0 (2.5-7.5) after a median of 10 months (range 5-18). In pwPMS MRI showed that 25% had active scans at baseline, and 0% at follow-up.

Conclusion: Personalised dosing of cladribine avoided severe lymphopenia in all but one patients and was very well tolerated across a large spectrum of disease severity. Our data suggests cladribine may offer benefit people with relapsing and progressive MS alike. The personalised protocol used appears safe, however warrants controlled studies to more definitively assess efficacy and safety, particularly in groups of pwMS who are not eligible for licensed DMT including oral cladribine (Mavenclad).
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http://dx.doi.org/10.1016/j.msard.2018.11.001DOI Listing
January 2019

Inclusion criteria used in trials of people with progressive multiple sclerosis.

Mult Scler 2020 03 15;26(3):279-283. Epub 2018 Oct 15.

Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK/Emergency Care and Acute Medicine Clinical Academic Group Neuroscience, The Royal London Hospital, Barts Health NHS Trust, London, UK.

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http://dx.doi.org/10.1177/1352458518803769DOI Listing
March 2020

Cladribine: Off-label disease modification for people with multiple sclerosis in resource-poor settings?

Mult Scler J Exp Transl Clin 2018 Apr-Jun;4(2):2055217318783767. Epub 2018 Jun 26.

BartsMS, Blizard Institute, Queen Mary University of London, United Kingdom.

Background: A considerable number of people with multiple sclerosis (pwMS) live in low- and middle-income countries (LMIC), where lack of resource adversely affects access to effective disease-modifying treatment.

Objective: The objective of this commentary is to propose a useful cost-effective disease-modifying treatment option for pwMS in LMIC with potential high efficacy and high convenience to the pwMS and treating physician.: We propose using generic 2-chloro-2'-deoxyadenosine (cladribine), a small molecule licensed for treatment of people with hairy cell leukaemia, as a solution of this significant equity imbalance. Cladribine has been shown in phase II and III trials to be a highly effective disease-modifying treatment for pwMS, and its adverse effect profile is comparable with any DMT currently licensed in high-income economies where an oral preparation has recently been licensed by the European Medicines Agency.

Conclusion: Our viewpoint takes into account experience we have gathered over the past three years in the use of generic cladribine to treat pwMS. Whilst here we focus on MS, there is significant potential for use of cladribine in other conditions that could benefit from its mechanism of action.
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http://dx.doi.org/10.1177/2055217318783767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077935PMC
June 2018

A phase II baseline versus treatment study to determine the efficacy of raltegravir (Isentress) in preventing progression of relapsing remitting multiple sclerosis as determined by gadolinium-enhanced MRI: The INSPIRE study.

Mult Scler Relat Disord 2018 Aug 28;24:123-128. Epub 2018 Jun 28.

Neuroscience and Trauma, Queen Mary University of London, Blizard Institute, Barts and the London School of Medicine and Dentistry, United Kingdom.

Background: Although the aetiology of multiple sclerosis (MS) remains elusive, it is clear that Epstein Barr virus (EBV) and possibly other viruses play a role in the pathogenesis of MS. Laboratory evidence suggests that human endogenous retroviruses (HERVs) could also have a role, but no interventional therapy has determined what will happen if HERVs are suppressed. Recent epidemiological evidence indicates patients with HIV infection have a significantly lower risk of developing MS and that HIV antiretroviral therapies may be coincidentally inhibiting HERVs, or other retroelements, that could be implicated in MS.

Objectives: To systematically investigate the effects of an HIV integrase strand inhibitor, raltegravir, on the number of gadolinium (Gd)-enhanced MRI lesions in people with active relapsing MS.

Methods: This is a Phase 2a clinical trial where twenty participants were enrolled in a 3 month baseline phase followed by 3 months of treatment with raltegravir 400 mg twice a day. Patients had monthly Gd-enhanced MRI, saliva collection to test for EBV shedding, blood sampling for safety monitoring, virology (including HERVs), measurement of immunological and inflammatory markers; and physical, neurological and quality-of-life assessments.

Results: All patients completed the six months trial period.The primary outcome measure of MS disease activity was the number of Gd-enhancing lesions observed, and raltegravir had no significant effect on the rate of development of Gd-enhancing lesions during the treatment phase compared with the baseline phase. Additionally, there was no change in secondary outcomes of either disability or quality-of-life measures that could reasonably be attributed to the intervention. There was a significant positive between HERV-W/MSRV (multiple sclerosis related virus) Gag Flix (Fluorescence index) B cells and the number of Gd-enhanced lesions at any visit (p = 0.029), which was independent of any potential influence of the trial drug administration. Regarding EBV shedding, there was no significant correlation between the amount of EBV shedding and the number of lesions. No change was detected in inflammatory markers (IL-8, IL-1β, IL-6, IL-10, TNF, IL-12p70 and HCRP), which were all within normal limits both before and after the intervention. Serum CD163 expression was also unchanged by raltegravir.

Conclusions: Raltegravir did not have any impact on MS disease activity. This could be due to the choice of antiretroviral agent used in this study, the need for a combination of agents, as used in treating HIV infection, the short treatment period or dosing regimen, or the lack of a role of HERV expression in MS once the disease is established. Borderline significance for the association between EBV shedding and the total number of lesions, probably driven by new lesion development, may indicate EBV shedding as a marker of inflammatory disease activity. In conclusion, interesting correlations between HERV-W markers, EBV shedding and new MRI lesions, independent from treatment effects, were found.
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http://dx.doi.org/10.1016/j.msard.2018.06.002DOI Listing
August 2018

Alemtuzumab depletion failure can occur in multiple sclerosis.

Immunology 2018 06 4;154(2):253-260. Epub 2018 Jan 4.

BartsMS, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK.

Alemtuzumab is a lymphocyte-depleting antibody and one of the most effective treatments for relapsing multiple sclerosis. However, it also causes loss of immune-tolerance leading to secondary autoimmunity and marked anti-drug antibody responses. Although these anti-drug responses have been reported to be of no significance, we hypothesized that they will affect the depleting capacity and treatment response in some individuals. This was found following analysis of the regulatory submission of the pivotal phase III trials, which was obtained from the European Medicines Agency. At the population level there was lack of influence of 'ever-positive' alemtuzumab-specific antibody responses on lymphocyte depletion, clinical efficacy and adverse effects during the 2-year trial. This was not surprising as no one before the first infusion, and only 0·6% of people before the second-infusion, had pre-infusion, neutralizing antibodies (NAbs). However, at the individual level, NAbs led to poor lymphocyte depletion. Importantly, it was evident that 31% of people had NAbs and 75% had binding antibodies at the end of treatment-cycle 2, which suggests that problems may occur in people requiring additional alemtuzumab cycles. In addition, we also identified individuals, following 'post-marketing' alemtuzumab use, whose lymphocyte level was never effectively depleted after the first infusion cycle. Hence, although alemtuzumab depletes lymphocytes in most individuals, some people fail to deplete/deplete poorly, probably due to biological-response variation and NAbs, and this may lead to treatment failure. Monitoring depletion following infusion and assessment of the neutralizing response before re-infusion may help inform the decision to retreat or switch therapy to limit treatment failure.
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http://dx.doi.org/10.1111/imm.12879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980120PMC
June 2018

Validation of an environmentally-friendly and affordable cardboard 9-hole peg test.

Mult Scler Relat Disord 2017 Oct 9;17:172-176. Epub 2017 Aug 9.

Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London, 4 Newark Street, London E1 2AT, UK.

Background: In multiple sclerosis (MS) upper limb neurological impairments, are an important driver of disability and handicap. The gold standard for assessing upper limb function is the 9-hole peg test (9HPT). One disadvantage of the current plastic version is its price, which prevents its widespread use as a self-monitoring tool by the MS community.

Objective: To develop and validate an affordable cardboard version of 9HPT for patients to self-monitor upper limb function at home. The aim is not to replace the plastic version, which would stay the gold standard in MS centers.

Methods: We enrolled 177 volunteers, 68 healthy controls and 109 people with MS (pwMS) at varying stages of their disease. Volunteers performed two trials of the 9HPT with their dominant hand and two with their non-dominant hand using both plastic 9HPT and cardboard 9HPT. The primary comparison parameter was the time needed to perform the task.

Results: The mean score for the cardboard 9HPT was 24.58 (SEM 1.54s) seconds compared to 26.03 (SEM 1.44s) seconds for the plastic 9HPT (p = 0.007). However, the two versions of the tests correlated very strongly, r = 0.96 (p < 0.001). The coefficient of variation, repeat-repeat testing, showed less variability with the cardboard version than in the plastic one with 10% and 14%, respectively. Two-thirds of pwMS preferred using the cardboard version.

Conclusion: This study demonstrates that the cardboard version is at least equivalent to the plastic version of the test with arguably better design attributes making it the preferred option for self-monitoring.
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http://dx.doi.org/10.1016/j.msard.2017.08.002DOI Listing
October 2017

Disease modification in advanced MS: Focus on upper limb function.

Mult Scler 2017 12 3;23(14):1956-1957. Epub 2017 Jul 3.

1 Blizard Institute (Neuroscience), Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, UK.

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http://dx.doi.org/10.1177/1352458517717811DOI Listing
December 2017

Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis.

EBioMedicine 2017 Feb 31;16:41-50. Epub 2017 Jan 31.

Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, United Kingdom. Electronic address:

Although multiple sclerosis (MS) is considered to be a CD4, Th17-mediated autoimmune disease, supportive evidence is perhaps circumstantial, often based on animal studies, and is questioned by the perceived failure of CD4-depleting antibodies to control relapsing MS. Therefore, it was interestingly to find that current MS-treatments, believed to act via T cell inhibition, including: beta-interferons, glatiramer acetate, cytostatic agents, dimethyl fumarate, fingolimod, cladribine, daclizumab, rituximab/ocrelizumab physically, or functionally in the case of natalizumab, also depleted CD19+, CD27+ memory B cells. This depletion was substantial and long-term following CD52 and CD20-depletion, and both also induced long-term inhibition of MS with few treatment cycles, indicating induction-therapy activity. Importantly, memory B cells were augmented by B cell activating factor (atacicept) and tumor necrosis factor (infliximab) blockade that are known to worsen MS. This creates a unifying concept centered on memory B cells that is consistent with therapeutic, histopathological and etiological aspects of MS.
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http://dx.doi.org/10.1016/j.ebiom.2017.01.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474520PMC
February 2017

Switching patients at high risk of PML from natalizumab to another disease-modifying therapy.

Pract Neurol 2016 Oct 25;16(5):389-93. Epub 2016 Apr 25.

Department of Neurosciences, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, UK Department of Neurology, Royal London Hospital, Barts Health NHS Trust, London, UK.

There are several options for switching people with multiple sclerosis (MS) who are at high risk of developing progressive multifocal leukoencephalopathy (PML) from natalizumab to alemtuzumab. However, some of these have risks that need to be managed, for example, the risks of carrying over asymptomatic PML from natalizumab on to the new therapy, and the risk of rebound disease activity associated with a prolonged washout after starting natalizumab. We propose a pragmatic bridging strategy, using another disease-modifying therapy (DMT), to reduce the risk of switching from natalizumab to alemtuzumab. We also discuss the caveats and subtleties associated with sequencing DMTs in MS and the complex decision making involved.
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http://dx.doi.org/10.1136/practneurol-2015-001355DOI Listing
October 2016

Recurrent cerebrospinal fluid escape in an HIV-1-infected patient receiving antiretroviral therapy.

AIDS 2016 Apr;30(7):1143-4

aDepartment of Neurology bDepartment of Neuroradiology, Centro Hospitalar do Porto, Porto, Portugal cNeuroimmunology Unit, Neuroscience and Trauma Centre, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, UK dClinical Immunology Unit, Centro Hospitalar do Porto, Porto, Portugal.

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http://dx.doi.org/10.1097/QAD.0000000000001037DOI Listing
April 2016

A brief history of the evolution of the medical research article.

Clujul Med 2015 15;88(4):567-70. Epub 2015 Nov 15.

Department of Modern Languages, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.

Given the current importance of publishing medical research articles in high-impact international journals, this article briefly presents key moments in the evolution of this reporting genre for a better understanding of the diachronic changes that have shaped it into a highly useful tool for creating and spreading knowledge, as well as for establishing academic hierarchies at both individual and institutional level. Therefore, focus will be placed not only on the evolution of its structure and purpose, but also on issues such as knowledge construction, knowledge claims, writer-reader interaction and the appropriate writing conventions and rhetorical strategies required for successful scientific communication.
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http://dx.doi.org/10.15386/cjmed-560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4689254PMC
January 2016

IgG4-related disease: a rare but treatable cause of refractory intracranial hypertension.

Pract Neurol 2016 Jun 11;16(3):235-9. Epub 2015 Dec 11.

Queen Mary University of London, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, UK.

Hypertrophic pachymeningitis secondary to IgG4-related disease is a rare but sometimes devastating cause of intracranial hypertension. It has the potential for an excellent response to corticosteroids or rituximab. We discuss the clinical presentation, imaging, histology (with its difficult distinction from lymphoma), management and follow-up of a case, including relapse and re-treatment following an initial response to rituximab.
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http://dx.doi.org/10.1136/practneurol-2015-001275DOI Listing
June 2016

No evidence for higher risk of cancer in patients with multiple sclerosis taking cladribine.

Neurol Neuroimmunol Neuroinflamm 2015 Dec 1;2(6):e158. Epub 2015 Oct 1.

Blizard Institute (Neuroscience) (J.P., G.D., M.M., D.B., K.S.), Queen Mary University of London, Barts and The London School of Medicine and Dentistry, London, UK; Oxford University Medical School (J.P.), John Radcliffe Hospital, Oxford, UK; London School of Hygiene and Tropical Medicine (D.R.A.), London, UK; Centre for Health Services Research (S.P.), Leeds Institute of Health Sciences, University of Leeds, Leeds, UK; Barts Health NHS Trust (B.P.T., M.M., K.S.), The Royal London Hospital, London, UK; Stem Cell Centre (G.J.), Lund University, Lund, Sweden; and Queen Square Multiple Sclerosis Centre (J.C.), Department of Neuroinflammation, UCL Institute of Neurology, University College London and National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London UK.

Objective: To compare the cancer risk of cladribine and other disease-modifying drugs (DMDs) in trials of people with relapsing multiple sclerosis (pwRMS).

Methods: Meta-analysis of phase III trials of licensed DMDs for pwRMS and a phase III trial of cladribine (CLARITY). Cancer rates were compared using Fisher exact test.

Results: Eleven trials were included. Investigated treatments included cladribine, dimethyl fumarate, fingolimod, teriflunomide, natalizumab, alemtuzumab, and glatiramer acetate. The cancer rate in the CLARITY treatment group (0.34%) was not increased compared to all other treatment groups, whether including placebo-controlled trials only (0.6%, p = 0.4631) or all trials, i.e., including those with an active comparator arm (0.67%, p = 0.3669). No cancer was reported in the CLARITY placebo group, whereas the combined cancer rate of all other placebo groups was 1.19% (p = 0.0159). The cancer rate of zero in the CLARITY placebo group was also lower than that in the phase III trial of cladribine in people with clinically isolated syndrome (ORACLE MS, 2.91%, p = 0.0012). In fact, no difference was detected between cancer rates in the treatment groups of CLARITY (0.34%) and ORACLE MS (0.49%) (p = 0.6546).

Conclusions: Our study does not support an increased cancer risk from cladribine in the doses used in CLARITY and ORACLE MS, which previously contributed to refusal of market authorization of cladribine in Europe. Longer-term follow-up is required to assess the safety profile of cladribine, as well as currently licensed DMDs, to definitively assess cancer risk.
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http://dx.doi.org/10.1212/NXI.0000000000000158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4592538PMC
December 2015

Is it time to target no evident disease activity (NEDA) in multiple sclerosis?

Mult Scler Relat Disord 2015 Jul 8;4(4):329-33. Epub 2015 May 8.

Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London, 4 Newark Street, London E1 2AT, UK; Department of Neurology, Royal London Hospital, Barts Health NHS Trust, London, UK. Electronic address:

The management of multiple sclerosis is becoming increasingly complex with the emergence of new and more effective disease-modifying therapies (DMT). We propose a new treatment paradigm that individualises treatment based on a choice between two interchangeable therapeutic strategies of maintenance-escalation or induction therapy. We propose treating- to-target of no evident disease activity (NEDA) as defined using clinical and MRI criteria. This algorithm requires active monitoring with a rebaselining MRI, at a point in time after the specific DMT concerned has had sufficient time to work, and at least annual MRI studies to monitor for subclinical relapses. Disease activity on the maintenance-escalation therapy arm of the algorithm indicates a sub-optimal treatment response and should trigger a discussion about switching, or escalating, therapy or the consideration of switching to the induction therapy arm of the algorithm. In comparison, disease activity on an induction therapy arm would be an indication for retreatment or a switch to the maintenance-escalation therapy arm. We envisage the definition of NEDA evolving with time as new technological innovations are adopted into clinical practice, for example the normalisation of whole, or regional, brain atrophy rates and cerebrospinal fluid neurofilament levels.
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http://dx.doi.org/10.1016/j.msard.2015.04.006DOI Listing
July 2015

Deep Sequencing of HIV-1 in Cerebrospinal Fluid.

Clin Infect Dis 2015 Sep 28;61(6):1022-5. Epub 2015 May 28.

Infection and Immunology, Barts Health NHS Trust Department of Medicine, Mildmay Hospital UK, London, United Kingdom.

Using deep sequencing, human immunodeficiency virus (HIV) resistance-associated mutations were detected as minority species in the cerebrospinal fluid (CSF) of 4 patients with higher HIV type 1 RNA load in CSF than in plasma, but not in 2 patients with higher plasma viral load. Deep sequencing could help our understanding of viral escape in the central nervous system.
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http://dx.doi.org/10.1093/cid/civ417DOI Listing
September 2015

Do neutralising antibodies against exogenous interferon-beta inhibit endogenous signalling pathways?

Mult Scler Relat Disord 2015 Jan 28;4(1):88-91. Epub 2014 Nov 28.

Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Blizard Institute, 4 Newark Street, London E1 2AT, England. Electronic address:

Introduction: Interferon-beta (IFNβ) is currently the most used disease-modifying treatment for relapsing-remitting multiple sclerosis (RRMS), but it can lead to the production of neutralising antibodies (NABs) against IFNβ.

Clinical Case: A lady with a past history of genital herpes was diagnosed with RRMS, started IFNβ treatment with a good initial response. Three years later her treatment was interrupted to become pregnant. After delivery she restarted IFNβ; she had more reactivations of genital herpes and experienced intermittent sensory symptoms often coinciding with herpes reactivation. High NABs titres against IFNβ were found. Since the introduction of famciclovir as prophylactic antiviral therapy and a switch from IFNβ to glatiramer acetate, herpes reactivations ceased and she had no further MS relapses.

Conclusion: Exacerbations of genital herpes coinciding with MS relapses suggest a potential link between the development of NABs and inhibition of anti-viral action of endogenous IFNβ. This case highlights that NABs not only decreases exogenous IFNβ treatment efficacy, but may also interfere with anti-viral properties of endogenous IFNβ. Investigating patients who are treated with biological medication will allow us to better understand the biology and signalling pathways in humans.
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http://dx.doi.org/10.1016/j.msard.2014.11.007DOI Listing
January 2015